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Cochrane for Clinicians
Putting Evidence into Practice
Screening for Prostate Cancer: Prostate-Specific Antigen
Testing Is Not Effective
NATHAN HITZEMAN, MD, and MICHAEL MOLINA, MD, MPH, Sutter Health Family Medicine Residency Program,
Sacramento, California
The Cochrane Abstract on
the next page is a summary of a review from
the Cochrane Library. It
is accompanied by an
interpretation that will
help clinicians put evidence into practice. Drs.
Hitzeman and Molina
present a clinical scenario
and question based on
the Cochrane Abstract,
followed by an evidencebased answer and a
critique of the review. The
practice recommendations in this activity are
available at http://www.
cochrane.org/reviews/en/
ab004720.html.
This clinical content conforms to AAFP criteria for
evidence-based continuing
medical education (EB
CME). See CME Quiz on
page 799.
The series coordinator
for AFP is Kenny Lin, MD,
Department of Family
Medicine, Georgetown
University School of Medicine, Washington, DC.
A collection of Cochrane
for Clinicians published
in AFP is available at
http://www.aafp.org/afp/
cochrane.
Clinical Scenario
A 51-year-old man with no significant family
history of cancer presents for a general health
examination. He asks if his testing should
include a prostate-specific antigen (PSA) test.
Administration in 1994 for prostate cancer
screening.6 Advocates of the test cite decreasing trends in prostate cancer mortality since
the test became available, and note that many
male urologists and primary care physicians
choose to have the test done on themselves.5
Clinical Question
However, a causal relationship between PSA
Does the PSA test have a role in prostate can- testing and decreased death from prostate
cer screening? Does it lead to better outcomes? cancer has not been well-established.
Established harms of PSA testing include
Evidence-Based Answer
excessive worry over false-positive results
Several large randomized controlled trials and morbidity from interventions, including
show that PSA screening does not signifi- infection, bleeding, pain, long-term sexual
cantly reduce prostate cancer mortality, even dysfunction, and urinary incontinence. A
in a U.S. study that included black men recent analysis showed that PSA testing does
and men with a family history of pros- not attain the likelihood ratios necessary to
tate cancer.1 However, PSA screening does qualify as a screening test, regardless of the
lead to overdiagnosis, overtreatment, and cutoff value used.7 The inventor of the PSA
treatment-associated morbidity.1,2 (Strength test said the test’s popularity has caused “a
of Recommendation = A, based on consis- hugely expensive public health disaster.” 6
The authors of this Cochrane review examtent, good-quality patient-oriented evidence)
ined whether PSA screening reduced prostate
Practice Pointers
cancer mortality.2 They identified five ranProstate cancer is the second leading cause of domized controlled trials involving a total
cancer death in U.S. men, with 32,050 deaths of 341,351 participants in the United States,
estimated in 2010 (11 percent of deaths in men Canada, and Europe. The meta-analysis—
with cancer).3 However, autopsy studies show whether viewed as a whole or by individual
that prostate cancer is detectable in one-half of study—showed that PSA screening conferred
men at 50 years of age and nearly 80 percent no benefit in prostate cancer mortality with
at 80 years of age.4 Although 16 percent of the exception of one subgroup in the Euromen will be diagnosed with prostate cancer pean Randomized Study of Screening for
during their lifetime, only 3 percent of all men Prostate Cancer. This subgroup of screened
die from prostate cancer.5 This discrepancy men 55 to 69 years of age had a relative risk
means that most men diagnosed with prostate reduction of 20 percent in prostate cancer
mortality after a mean follow-up of nine
cancer will not die from the disease.
The goal of cancer screening is detection years. Although this sounds encouraging, the
of tumors in asymptomatic persons at a stage small absolute benefit translates to 1,410 men
that permits more timely and effective inter- needing to be screened and 48 men needventions than if detected clinically. The PSA ing to be diagnosed to prevent one prostate
test was approved by the U.S. Food and Drug cancer death over a decade. Additionally, it
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Cochrane Abstract
Background: Any form of screening aims to reduce disease-specific and
overall mortality and improve a person’s future quality of life. Screening for prostate cancer has generated considerable debate within the
medical and broader community, as demonstrated by the varying recommendations made by medical organizations and governed by national
policies. Much of this debate is caused by the limited availability of highquality research and the influence of false-positive or false-negative
results generated by use of the screening techniques, such as the digital
rectal examination and prostate-specific antigen (PSA) blood test. Our
2006 Cochrane review identified insufficient evidence to support or
refute the use of routine mass, selective, or opportunistic screening for
prostate cancer. This article is an update of that review.
Objectives: To determine whether screening for prostate cancer
reduces prostate cancer–specific mortality, all-cause mortality, and its
impact on quality of life, including adverse events.
Search Strategy: An updated search of electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled
Trials, Medline, EMBASE, CANCERLIT, and the NHS EED) was performed,
in addition to hand searching of specific journals and bibliographies in
an effort to identify published and unpublished trials.
Selection Criteria: All randomized controlled trials (RCTs) of screening
versus no screening for prostate cancer were eligible for inclusion in this
review.
Data Collection and Analysis: The authors assessed eligibility and
trial quality, and extracted and double-entered data.
Main Results: Five RCTs with a total of 341,351 participants were
included in this review. All involved PSA testing, although the interval and
threshold for further evaluation varied across trials. The age of participants ranged from 50 to 74 years, and duration of follow-up from seven to
15 years. The methodological quality of three of the studies was assessed
as posing a high risk of bias. Analysis of the five studies showed no
statistically significant reduction in prostate cancer–specific or all-cause
mortality among the whole population of men randomized to screening
versus controls. A preplanned analysis of a core age group of men 55 to
69 years of age from the largest trial (European Randomized Study of
Screening for Prostate Cancer [ERSPC]) reported a significant 20 percent
relative reduction in prostate cancer–specific mortality; (95% confidence
interval [CI], 0.65 to 0.98; absolute relative risk = 0.71 per 1,000 men).
Meta-analysis of the five included studies indicated no statistically significant difference in prostate cancer–specific mortality between men
randomized to screening and control (relative risk [RR] = 0.95; 95% CI,
0.85 to 1.07). Subgroup analyses indicated that prostate cancer-specific
mortality was not affected by the age at which participants were
screened. Meta-analysis of two studies investigating all-cause mortality
did not determine any significant differences between men randomized
to screening or control (RR = 1.00; 95% CI, 0.98 to 1.02). A diagnosis of
prostate cancer was significantly greater in men randomized to screening compared with those randomized to control (RR = 1.35; 95% CI,
1.06 to 1.72). None of the studies provided detailed assessment of the
effect of screening on quality of life or costs associated with screening.
Harms of screening included high rates of false-positive results for the
PSA test (up to 75.9 percent), overdiagnosis (up to 50 percent in the
ERSPC study) and adverse events associated with transrectal ultrasoundguided biopsies, such as infection, bleeding, and pain.
Authors’ Conclusions: Prostate cancer screening did not significantly
decrease prostate cancer–specific mortality in a combined meta-analysis
of five RCTs. Only one study (ERSPC) reported a benefit in a subgroup
of men 55 to 69 years of age. Within this subgroup of men, it was
determined that 1,410 men needed to be invited to screening, and 48
additional men subsequently diagnosed with prostate cancer needed
to receive early intervention, to prevent one additional prostate cancer
death at 10 years. Men should be informed of this and the demonstrated
adverse effects when deciding whether to undertake screening for prostate cancer. Any benefits from prostate cancer screening may take up to
10 years to accrue; therefore, men who have a life expectancy less than
10 to 15 years should be informed that screening for prostate cancer is
unlikely to be beneficial.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library.
Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an
official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
is possible that this study had publication
bias—the Swedish arm of the study reported
a relative risk reduction of 50 percent, which
is far greater than at any of the other sites.
If the Swedish results are excluded from the
analysis, the mortality benefit of PSA screening reported in the trial disappears.
The U.S.-based Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial followed
76,693 men over seven years and found a statistically nonsignificant, 13 percent increase
in prostate cancer mortality in men randomized to be invited to screening.1 This large
trial is more applicable to U.S. men, given
the PSA cutoff of 4 ng per mL (4 mcg per L)
and the annual screening interval (some of
the European sites used lower cutoffs and
less frequent testing). Although some have
concerns about the extensive crossover that
April 1, 2011
◆
Volume 83, Number 7
occurred in this study—nearly one-half of
the control group obtained at least one PSA
test during the study period—no study of
this scale is perfect.
The similarly large Women’s Health Initiative trial had crossovers in results for
postmenopausal hormone replacement
(40 percent discontinuation of study drugs
in the active arm and 10 percent initiation in
placebo-assigned women), but its conclusions
about the risks and benefits of the intervention were still considered to be definitive.8
Based on this evidence, PSA testing should
not be used for prostate cancer screening
in low-risk men. Current guidelines from
the American Urological Association and
the American Cancer Society recommend
that physicians discuss PSA screening with
patients.2 The U.S. Preventive Services Task
www.aafp.org/afp
American Family Physician 803
Cochrane for Clinicians
Force provides no recommendation for or
against PSA screening apart from discouraging its use in men 75 years and older, although
it is currently updating its 2008 recommendations.2 The United Kingdom disallows PSA
testing for prostate cancer screening.2
In light of the controversy regarding PSA
screening, most guidelines encourage a
shared decision-making approach between
the patient and physician.2 A booklet about
prostate cancer screening for patients is provided through the Centers for Disease Control and Prevention at http://www.cdc.gov/
cancer/prostate/pdf/prosguide.pdf. How to
fit this discussion into a 15- to 30-minute
office visit remains a challenge when most
patients are already sold on the benefits of
cancer screening. In a busy practice, it is
sometimes easier to fulfill a request for a PSA
test. However, in doing so, physicians may
be doing harm by exposing their patients
to unacceptably high risks of false-positive
results, overdiagnosis, and adverse effects of
unnecessary treatment for indolent cancers.
Address correspondence to Nathan Hitzeman, MD, at
[email protected]. Reprints are not available
from the authors.
Author disclosure: Nothing to disclose.
REFERENCES
1.Andriole GL, Crawford ED, Grubb RL III, et al.; PLCO
Project Team. Mortality results from a randomized
prostate-cancer screening trial [published correction
appears in N Engl J Med. 2009;360(17):1797]. N Engl J
Med. 2009;360(13):1310-1319.
2.Ilic D, O’Connor D, Green S, Wilt T. Screening for
prostate cancer. Cochrane Database Syst Rev. 2010;
(9):CD004720.
3.Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010.
CA Cancer J Clin. 2010;60(5):277-300.
4.Sakr WA, Grignon DJ, Haas GP, Heilbrun LK, Pontes JE,
Crissman JD. Age and racial distribution of prostatic
intraepithelial neoplasia. Eur Urol. 1996;30(2):138-144.
5.McCormick KA, Osman NY, Pomerantz MM. Update
on prostate cancer screening. J Clin Outcomes Manage.
2010;17(10):470-479.
6.Ablin RJ. The great prostate mistake. The New York
Times. March 9, 2010. http://www.nytimes.com/2010/
03/10/opinion/10Ablin.html?_r=1. Accessed February
14, 2011.
7.Holmstrom B, Johansson M, Bergh A, Stenman UH,
Hallmans G, Stattin P. Prostate specific antigen for early
detection of prostate cancer: longitudinal study. BMJ.
2009;339:b3537.
8.Manson JE, Hsia J, Johnson KC, et al.; Women’s Health
Initiative Investigators. Estrogen plus progestin and
the risk of coronary heart disease. N Engl J Med.
2003;349(6):523-534. ■
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